DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants' arguments, filed 01/20/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103--Previous
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5, 8, 12, 15, 17, 23, 25, 27, 32, 35-36,39, 41-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weinstein et al., (WO 2018/022668). This rejection applies to newly added claim 56.
Weinstein et al. teaches “methods for treating a subject having or at risk of developing cancer by administering a neuromodulation agent” (Abstract), “wherein the neuromodulating agent is a blocking antibody against . . . artemin . . . “ (p. 318, Claim 75). The method further comprises administering a second therapeutic agent “wherein the second therapeutic agent is a checkpoint inhibitor” (p. 321, Claim 106), wherein suitable checkpoint inhibitors include “an inhibitor of PDL1” (p. 321, Claim 107).
Further, “[a][nother type of agent that can be administered in combination with a neuromodulating agent is a therapeutic agent that is a non-drug treatment”, e.g. “the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and/or surgical excision of tumor tissue” (p. 234, lines 3-5).
“In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559) (p. 239, lines 18-20), as per claims 5 and 8.
Since the prior art teaches combination therapies to treat cancer in patients, as claimed, the artisan would have reasonably expected an enhanced anti-tumor effect compared to administration of radiotherapy or PD-LI inhibitor alone, as per claim 56.
Reversing Ter-cell-mediated resistance to the radiotherapy and/or PD-LI inhibitor, would have been the result of the combination therapy, as taught by Weinstein.
In regard to claim 15, Weinstein et al. teaches, “the neuromodulating agent is a component of a gene editing system” (p. 216, lines 40-41), wherein “[e]xemplary gene editing systems include zinc finger nucleases (ZFNs), Transcription Activatory-Like Effector-based Nucleases (TALEN), and the clustered regulatory interspaced short palindromic repeat (CRISPR) system” (p. 217, lines 5-8), wherein “the CRISPR system includes the Cas9 protein, a nuclease that cuts on both strands of the DNA” (p. 217, lines 22-23).
In regard to claim 27, Weinstein et al. teaches that the type of cancer to be treated is “small cell lung cancer (SCLC)” (p. 2, line 4-5).
In regard to administration Weinstein et al. teaches:
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(p. 234, lines 6-13). Accordingly, it would have been obvious to administer the checkpoint inhibitor and/or the inhibitor of the artemin pathway subsequent to the start of radiotherapy, as per claim 25, or simultaneously, as per claim 27 or 32, or 36.
The neuromodulating agent may be administered “once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three time weekly, once biweekly, once monthly, once bimonthly, twice a year, or once yearly” (p. 243, lines 1-11), as per claim 35. “Subjects may be treated for a discrete period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) or until the disease or condition is alleviated, or treatment may be chronic depending on the severity and nature of the disease or condition being treated” (Id.), as per claim 35.
The neuromodulating agent may be administered “intratumorally” (p. 320, Claim 104), as per claim 39.
In regard to claim 41, Weinstien et al. teaches, “According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., small cell lung cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression” (p. 253, lines 16-18; see also p. 311, Claim 7).
The instant prior art does not appear to provide sufficient specificity, i.e., involves too much “picking and choosing” to give rise to anticipation. See, Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). That being said, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect…. the combination is obvious”. KSR v. Teleflex, 127 S,Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). Consistent with this reasoning, it would have obvious to have selected the various combinations of features claimed from within the prior art disclosure, i.e. administration of one of radiotherapy (radiation therapy), a checkpoint inhibitor and an effective amount of an inhibitor of the artemin pathway, to arrive at the instantly claimed compositions.
2) Claim(s) 21 and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weinstien et al., (WO 2018/022668) as applied to claim 1 and 17 above, and further in view of Andrews et al., (WO 2018/136663).
Weinstein et al., which is taught above, differs from claims 21 and 42 insofar as it does not teach where the inhibitor of the artemin pathway is LOXO-292.
Andrews et al. teaches use of RET inhibitors for “treating cancer and/or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment” (p. 2, para. [0012]). Lung cancer is a RET-associated cancer (p. 68, para. [00604]). “RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotropic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN) and persephin (PSPN)” (p. 1, para. [0004]).
The method includes “administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of . . . LOXO-292 . . .” (p. 170, para. [00723]).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to include LOXO-292 in the method of Weinstein et al. for the advantage of treating cancer. The artisan would have had a reasonable expectation of success with the combination insofar as RET-associcated cancers include the same type of cancer disclosed in Weinstein et al., e.g., lung cancer, as well as inhibition of artemin. Accordingly, LOXO-292 would have sufficed as a neuromodulating agent in Weinstein et al.
Technological Background
The prior art made of record and considered pertinent to applicant's disclosure Banerjee (Thesis: The University of Auckland 2013). Banerjee is pertinent for teaching ARTEMIN stimulates radio- and chemo-resistance by TWIST1-BCL-2 dependent cancer stem cell-like behavior in mammary carcinoma cells (p. 90). “ARTEMIN (ARTN) is one member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (211). ARTN has previously been demonstrated to be involved in progression of various carcinomas (34, 36, 288) including mammary carcinoma (211). Increased ARTN expression in mammary carcinoma promotes metastasis (188), radio-resistance (manuscript submitted), chemo-resistance (245), endocrine resistance (190) and also enhances CSC [cancer stem cell] like activity in estrogen receptor negative mammary carcinoma (ER-MC) (manuscript submitted). Interestingly, another neurotrophic factor, nerve growth factor (NGF), also stimulates tumour angiogenesis in vivo in mammary carcinoma via the P13K-AKT pathway (289). Similarly, ARTN could potentially modulate not only tumour growth and metastasis, but also promote angiogenesis as a contribution to tumour progression leading to poor survival outcomes in ER-MC (188)” (p. 125, 1st paragraph).
Response to Arguments
i) Applicant argues, “Weinstein provides no teaching, suggestion, or motivation to select artemin from among numerous candidates, nor any reasonable expectation that inhibiting artemin would enhance radiotherapy or immune checkpoint therapy” (p. 8).
The Examiner disagrees.
It is well settled that it is obvious for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as the prior art teaches that the selection will result in the disclosed effect. See Merck & Co., v. Biocrafi Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) ("That the '813 patent discloses a multitude of effective combinations does not render any particular formulation less obvious."); See also In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985) (affirming obviousness rejection of claims in light of prior art teaching that "hydrated zeolites will work" in detergent formulations, even though "the inventors selected the zeolites of the claims from among 'thousands' of compounds"). In this case, the selection of ARTEMIN from the list of neurotrophic factors to be blocked or inhibited by antibody is not less obvious because it is part of a list.
ii) Applicant argues, “Weinstein does not teach or suggest the unexpected syngergistic results of the enhanced therapeutic efficacy of radiotherapy and PD-L1 blockade after the disruption of the Ter-cell/artemin axis” (p. 9)
However, the prior art unambiguously teaches using antibodies to inhibit ARTEMIN for the purposes of treating cancer. The fact that applicant has recognized another advantage, i.e. reversing Ter-cell mediated resistance, which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The specification states, “It was found that splenectomy produced synergistic effects with both IR and PD-L1 blockade on reducing artemin levels (Figure 51). This is the only mention of synergy in the specification. Figure 51 is shown below:
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Figure 51 measures the amount of ARTN in mice serum following treatment with IR and PD-L1, for mice with spleen (Sham) and mice without spleen (splenectomy). The mice receiving the splenectomy had significantly lower serum artemin levels, however, synergy is the combined action of two or more agents that produces a total effect greater than the sum of their individual effects. However, these results are not surprising since the artemin is produced in the spleen by Ter-cells. One would reasonably expect splenectomy to result in a significant loss of serum artemin.
In regard to the unexpected results, the specification states, “The present inventors have unexpectedly discovered that combining radiotherapy or checkpoint inhibitor immunotherapy with artemin pathway blockade significantly enhances the effect of both radio- and immunotherapies compared to monotherapy or a combination of radiotherapy and immunotherapy alone” (p. 22-23, para. [00121]).
However, at the time of applicant’s filing it was known that ARTEMIN (ARTN) stimulates radio- and chemo-resistance in cancer cells, as taught by Banerjee. Banerjee teaches the mechanism behind the resistance and recommends use of antibodies for therapy, “I would further consider developing anti-ARTN antibodies for therapeutic treatment purposes” (see p. 153, Future directions). Accordingly, applicant’s results showing inhibition of ARTN as a means for reversing resistance to radiotherapy and/or PD-L1 inhibitor therapy would have been expected, since the ARTEMIN is responsible for radio- and chemo- resistance in cancer cells, as taught by Banerjee.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER E WEBB whose telephone number is (571)270-3287 and fax number is (571) 270-4287. The examiner can normally be reached from Mon-Fri 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612